Fosaprepitant dimeglumine (Ia) is an antiemetic drug for intravenous administration. It is supplied as a sterile, lyophilized powder in a sealed vial under the trade name EMEND for injection by Merck and Co., Inc. Each vial of EMEND for injection contains 245.3 mg of fosaprepitant dimeglumine equivalent to 150 mg of fosaprepitant free acid and the following inactive ingredients: edetate disodium (18.8 mg), polysorbate 80 (75 mg), lactose anhydrous (375 mg), sodium hydroxide and/or hydrochloric acid (for pH adjustment).
Fosaprepitant dimeglumine (Ia) is a white to off-white amorphous powder with a molecular weight of 1004.83. It is freely soluble in water, which makes it particularly suitable for aqueous based intravenous administration. The active ingredient, fosaprepitant, is chemically known as {3-[2(R)-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)morpholin-4-yl]methyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl}phosphonic acid (Formula I, hereinafter “I”). The structures of fosaprepitant dimeglumine (Ia) and fosaprepitant free acid (I) are depicted as follows:

Fosaprepitant dimeglumine (Ia) and fosaprepitant free acid (I) are both a prodrug of aprepitant (formula III, hereinafter “III”), which has the following structure:

When EMEND for injection is administered via an intravenous infusion, fosaprepitant is rapidly converted in the body to aprepitant. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin-1 (NK1) receptors. EMEND for injection, in combination with other antiemetic agents, is indicated in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin and for the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).
U.S. Pat. No. 7,915,407 discloses a process for the preparation of fosaprepitant dimeglumine. The entire content of this patent is incorporated herein by reference. The patented process comprises the steps of isolating monobenzyl{3-[2(R)-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)morpholin-4-yl]methyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl}phosphonic acid (hereinafter, “monobenzyl fosaprepitant”) followed by subjecting the monobenzyl fosaprepitant to hydrogenation in a cosolvent system of methanol and water in the presence of palladium on carbon and N-methyl-D-glucamine to yield fosaprepitant dimeglumine.
U.S. Pat. No. 8,623,844 discloses another process for the preparation of fosaprepitant dimeglumine, the entire content of which is incorporated herein by reference. According to the patent, fosaprepitant dimeglumine may be prepared by (1) isolation of dibenzyl{3-[2(R)-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)morpholin-4-yl]methyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl}phosphonic acid (hereinafter, “dibenzyl fosaprepitant”), (2) hydrogenation of dibenzyl fosaprepitant in a solvent system of methanol and water in the presence of palladium on carbon and N-methyl-D-glucamine to yield crude fosaprepitant dimeglumine, and (3) purification of crude fosaprepitant dimeglumine.
U.S. Patent Application Publication No. 20140107337 discloses a slightly different process for preparing fosaprepitant dimeglumine from that of U.S. Pat. No. 8,623,844. The entire content of this publication is incorporated herein by reference to this application. According to the publication, fosaprepitant dimeglumine can be prepared by subjecting dibenzyl fosaprepitant to hydrogenation in a solvent system of methanol in the presence of palladium on carbon, N-methyl-D-glucamine, and a silica bond metal scavenger. It is reported that, as result of using the silica bond metal scavenger, the resulting fosaprepitant dimeglumine product has a lower content of palladium.
Since fosaprepitant dimeglumine salt is highly hygroscopic in nature, it is difficult to subject fosaprepitant dimeglumine salt to purification (e.g. crystallization) on a large scale. However, purification of the precursors of fosaprepitant dimeglumine (i.e., intermediates) produced in the prior art processes is neither ideal nor practical. For example, dibenzyl fosaprepitant is not very stable and prone to an instantaneous conversion to monobenzyl fosaprepitant. Monobenzyl fosaprepitant is more stable than dibenzyl fosaprepitant but it is difficult to remove all of synthetic impurities and unused reagents from the solid of monobenzyl fosaprepitant. Additionally, fosaprepitant is prepared by catalytic hydrogenation of dibenzyl fosaprepitant or monobenzyl fosaprepitant using palladium (Pd) on carbon as a catalyst, as disclosed in the prior art. The Pd catalyst needs to be removed from fosaprepitant after the hydrogenation in order to obtain a product suitable for pharmaceutical use. But the poor stability of fosaprepitant makes the removal of the Pd catalyst very challenging.
Thus, there remains a need in the industry to provide an improved process for the preparation of fosaprepitant dimeglumine with high purity that is amenable for a commercial scale synthesis.